A Nitrous oxide is a gas that, when inhaled by dental patients, reaches the brain quickly to provide sedative and analgesic effects. It relieves fear and has a morphine-like effect that mutes pain reactions and anxiety associated with pain. Its actions are short lived, so once a patient stops breathing nitrous oxide, its effects dissipate right away, allowing adult patients to drive themselves home.

QWhat are the ramifications of prolonged exposure to nitrous oxide?

A Nitrous oxide oxidizes the cobalt atom of vitamin B12 that is bound to methionine synthase, an enzyme necessary for the synthesis of DNA and the myelination of nerves. Excessive nitrous oxide exposure causes the enzyme to become permanently inactivated, and new enzyme must be synthesized to replace it. For people with vitamin B12 deficiency, exposure to nitrous oxide may cause pernicious anemia (anemia caused by vitamin B12 deficiency) because the pathway that methionine synthase supports no longer functions. Breathing a high concentration of nitrous oxide for even a relatively short period of time can alter methionine synthase. For example, when a patient is given 30% nitrous oxide for 3 hours, he or she loses about half of the enzyme’s activity. Although it may take several days for the new enzyme to be synthesized, most people can tolerate this loss easily. But in the 1950s nitrous oxide was tested as an analgesic where post-surgical patients were placed in a room containing analgesic concentrations of nitrous oxide. This practice caused anemia after several days and was abandoned. Methionine synthase is also susceptible to damage by chronic exposure to subtherapeutic concentrations of nitrous oxide. This is why scavenging equipment is used on nitrous oxide machines to protect dental personnel.

A Relationship with Autism

Q Is nitrous oxide unsafe to use on patients with autism?

A There is currently no direct evidence that nitrous oxide poses special risks for autistic patients. However, some physicians who subscribe to the “Defeat Autism Now!”(DAN!) philosophy of autism management have expressed concern that people with autism who receive nitrous oxide for dental treatment may be adversely affected by the gas. Methionine synthase is part of a larger biochemical pathway that involves folic acid metabolism. According to DAN! physicians, many people with autism may have an abnormality involving vitamin B12 or folate. Although this concern has not appeared yet in the established medical literature, it is heavily discussed online in autism forums and websites, and dental professionals should be aware of it. We’re starting to see parents of patients with autism asking that nitrous oxide not be used.

Q If the research is limited, how are people becoming aware of this concern?

A The concern about nitrous oxide and folic acid metabolism may have originated from a single case report that actually had nothing to do with autism. It involved a 3-month-old patient in the late 1980s who received nitrous oxide for about 30 minutes as part of a general anesthetic given for a biopsy procedure.1 The biopsy was positive for cancer, and the tumor was subsequently removed in a 2-hour procedure for which nitrous oxide was again given as part of the general anesthetic. The surgery was successful and the patient was sent home. The patient was re-admitted to the hospital 17 days later with progressive neurologic damage, and he died 4 weeks later despite intensive therapy. When his blood samples were studied, a severe problem with folate metabolism was found. In 2003, this patient’s tissues were re-examined with new technology and the patient turned out to have a huge defect on the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). It is believed that the patient died because the nitrous oxide exposures worsened the biochemical derangement in folate metabolism that was pre-existing in the patient. His body could not make DNA properly and he couldn’t make myelin (which surrounds nerves), and both deficits probably contributed to his neural degeneration.
Very recently, evidence has been published that people with autism may have a relatively high incidence of problems with this enzyme.2 However, many people with autism have a normal enzyme profile, just as many people without autism have reduced enzyme activities.

Q Is nitrous oxide often used on patients with autism in the dental office?

A Treating children with autism in the dental office can be difficult because often they are not cooperative. Dental professionals have traditionally used nitrous oxide as a common sedative. There is no proof that nitrous oxide is harmful to use on patients with autism. But because the concern is there and parents of children with autism may be aware of it, dental professionals need to be prepared. At this time, parents should be advised that any risk from nitrous oxide is minimal. Another method of sedation may be suggested if they are adamant against the use of nitrous oxide.

Q What is your assessment of the risk in treating these patients with nitrous oxide?

A There is no scientific evidence that treating a child for 30 minutes with nitrous oxide at 30% or 40% poses any risk. However, I cannot say that children who have a significant defect in this particular enzyme are not at risk. The incidence of a severe defect as identified in the infant described previously is very rare. Most children with autism undoubtedly do not have a defect of this nature.
Although gene variants that make MTHFR less stable with time are common, people with these variants will still have enough enzyme to avoid problems. There are some potentially lethal mutations that people survive under normal circumstances, but if hit with a real challenge and nitrous oxide might be a challenge for them, then they can have a major problem. The ability to detect enzyme deficiencies is a relatively recent innovation, so more will be discovered about it in the future.

Q Is nitrous oxide safe to use on children in general?

A It’s an extremely effective technique for kids, particularly for older kids. It’s not as effective for younger children because, if they cry, they “blow off” the nitrous oxide and the effect is lost. Nevertheless, countless numbers of children, both young and older, have been treated successfully with nitrous oxide. In my opinion, the administration of nitrous oxide is probably safer for children than is giving local anesthesia.
Dosages for Children

Q Does nitrous oxide provide enough anesthesia to use while a child undergoes restorative treatment?

A Not reliably. For restorative procedures, a local anesthetic should be used in concert with nitrous oxide. Nitrous oxide relieves discomfort but the pain will remain during an intensive procedure, and a child will react to the pain.

Q How do the dosages differ when giving children nitrous oxide?

A An adult will be adequately sedated with a concentration of around 30% to 40%. In young children, a higher concentration is often given initially to get a stronger effect. The local anesthetic is then administered, and the nitrous oxide concentration is reduced to the adult level. The maximum that the nitrous oxide machine should be able to deliver is 70% nitrous oxide. At least 30% oxygen should always be administered.

Q What is the technique for the safe administration of nitrous oxide to children?

A The oxygen should be administered alone, with its volume adjusted so that the reservoir bag is not fully inflated nor fully deflated. You should be able to see the reservoir bag contract and expand with each breath of the child, and it should stay partially inflated at all times. Once you’ve determined that, you should start to incrementally administer nitrous oxide while simultaneously reducing the amount of oxygen delivered. Some machines allow you to adjust the percentage of nitrous oxide or oxygen by simply dialing the desired percentage of gas while automatically keeping the total gas flow constant. Others have independent controls for each gas. In this case, you would increase the amount of nitrous oxide by a small amount, eg, a half liter per minute, while simultaneously reducing the oxygen delivery by the same amount, continuing this process until the desired concentration is reached. At the end of the procedure the nitrous oxide is turned off, and the oxygen is adjusted to the original total gas flow. Breathing pure oxygen for several minutes will help flush the nitrous oxide machine and tubes and decrease nitrous oxide pollution of the dental operatory.

About Autism

Definition
Autism is a neurodevelopmental disorder that results in reduced social interaction, communication problems, and significantly limited or repetitive interests.1 It is the most common in a group of disorders called autism spectrum disorders, which affect people in varying degrees. The disorder typically appears within the first 3 years of life.2 Current estimates put autism’s rate of incidence at one in 150 children in the United States, with boys experiencing a higher rate of diagnosis—approximately one in 94.2 The cause of autism is unknown, although both genetics and environment appear to play a role.3

Common Symptoms
Autism characteristics can range from mild to severe and include three main behaviors: problems with social interaction, reduced verbal and nonverbal communication skills, and very focused interests or repetitive behavior.1

Dental Implications
A visit to the dental office is often intimidating for children but it can be terrifying for children with autism. First, the parents should be consulted for specific advice on how to achieve a successful office visit. Children with autism may need to be introduced to the dental office before any treatment is planned. Children with autism should be approached quietly. Reinforcement of positive behavior is recommended.4 Throughout the dental appointment, the dental professional should show and discuss what is happening and what is coming next. Noise and sudden movement should be minimized if possible.3 If behavior modification is unsuccessful, then general anesthesia may be required.4

John A. Yagiela, DDS, PhD, is professor and chairman of the Division of Diagnostic and Surgical Sciences at the University of California, Los Angeles (UCLA), School of Dentistry and professor of Anesthesiology in the David Geffen School of Medicine at UCLA. He is actively engaged in research on pain and anxiety control and maintains a part-time practice limited to dental anesthesiology.